Schwann cell activation in oral cancer perineurial invasion and neuropathic pain

雪旺细胞激活在口腔癌神经周围侵犯和神经性疼痛中的作用

基本信息

批准号：
10597995
负责人：
Yi Ye
金额：
$ 37.86万
依托单位：
NEW YORK UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10597995
关键词：
Address Afferent Neurons Animal Behavior Animal Model Axon Behavior Cancer Cell Growth Cancer Patient Cell Culture Techniques Cells Cellular biology Clinical Trials Coculture Techniques Colon Carcinoma Data Disease Progression Electrophysiology (science)Etiology Functional disorder Gene Deletion Goals Grant Growth Human Hypersensitivity Immune System Diseases Impairment Interruption Invaded Knowledge Link Malignant Neoplasms Malignant neoplasm of pancreas Mechanics Mediating Mediator Modeling Mus Myelin Nerve Nerve Degeneration Nerve Regeneration Neuroglia Neurons Nociception Nociceptors Oncology Opioid Oral Pain Pain Clinics Pain management Pathology Patients Peripheral Peripheral Nerves Process Prognosis Proliferating Quality of life Recombinants Reporting Research Role Schwann Cells Severities TNF gene Testing Tissues Tropism Tumor Necrosis Factor Receptor axon injury cancer cell cancer invasiveness cancer pain carcinogenesis cell type comorbidity cytokine improved in vivo inhibitor intense pain malignant mouth neoplasm migration myelination nerve injury nervous system disorder novel strategies novel therapeutics oral pain overexpression painful neuropathy perineural receptor receptor expression repaired response response to injury side effect statistics therapeutic evaluation tumor tumor progression

项目摘要

PROJECT SUMMARY/ABSTRACT Oral cancer patients suffer from pain with impaired oral function. Oral cancer pain is initiated and maintained in the periphery and worsens during cancer progression. Perineural invasion (PNI), defined as cancer invading in, around, or along the nerve, correlates with increased pain severity and poor prognosis. Treatment options for pain are limited. No targeted treatments for PNI exist. Current research on oral cancer pain mainly focuses on the effect of cancer mediators on primary afferent neurons. Neuropathic pain caused by PNI is rarely addressed mechanistically. The role of Schwann cells (SCs), the most prevalent cell type supporting peripheral nerves, has not been defined in oral cancer PNI and pain. We found that oral cancer induces SC activation, a well-known response of SCs to nerve injury. Oral cancer cells and SCs mutually promote proliferation, migration, and invasion. Supernatant from oral cancer-activated SCs induces nociceptive behaviors in mice. We found that oral cancer cells are enriched with the soluble form of tumor necrosis factor (sTNF), a master regular of cytokines. sTNF is known to activate SCs and mediates neuropathic pain. The primary receptor for sTNF is TNFR1. We hypothesize that sTNF activates SCs through TNFR1 to promote oral cancer PNI and neuropathic pain. Our hypothesis is based on our observations in patients, cell culture and animal models of oral cancer and PNI. This proposal will combine expertise from oncology, pathology, electrophysiology, cell biology, nerve ultrastructure, animal behavior, and statistics to: Aim 1. Evaluate associations between SC activation, SC TNFR1 expression, PNI, and pain in human oral cancer. Aim 2. Characterize the effect of sTNF neutralization or SC TNFR1 gene deletion on oral cancer pain. We will determine whether sTNF-TNFR1 mediates SC activation, which causes SCs to release nociceptive mediators, and/or is accompanied by myelin/axon abnormalities, resulting in nociceptor hypersensitivity and neuropathic pain. Aim 3. Characterize the effect of sTNF neutralization or SC TNFR1 gene deletion on oral cancer PNI. We will test whether sTNF- TNFR1 mediated SC activation facilitates proliferation, migration, and invasiveness between SCs and oral cancer cells, promoting PNI. Our objective is to elucidate the mechanism of SC activation and to test the therapeutic potential of controlling SC activation to reduce oral cancer PNI and pain. Understanding how SCs contribute to oral cancer PNI and neuropathic pain may reveal new opportunities and strategies to interrupt these co-morbidities of oral cancer.

项目概要/摘要口腔癌患者因口腔功能受损而遭受疼痛。口腔癌疼痛开始并持续于周围并在癌症进展过程中恶化。神经周围侵犯（PNI），定义为癌症侵入，围绕或沿着神经，与疼痛严重程度增加和预后不良相关。治疗方案疼痛是有限的。尚无针对 PNI 的靶向治疗方法。目前口腔癌疼痛的研究主要集中在癌症介质对初级传入神经元的影响。 PNI 引起的神经性疼痛很少见机械地解决。雪旺细胞 (SC) 是最常见的支持外周细胞的细胞类型，其作用神经，尚未定义口腔癌 PNI 和疼痛。我们发现口腔癌会诱导 SC 激活，这是一种 SC 对神经损伤的众所周知的反应。口腔癌细胞和SCs相互促进增殖，迁徙、入侵。口腔癌激活的 SC 上清液会诱导小鼠出现伤害性行为。我们发现口腔癌细胞富含可溶形式的肿瘤坏死因子 (sTNF)，这是一种主要的细胞因子的规律。已知 sTNF 可以激活 SC 并介导神经性疼痛。主要受体 sTNF 是 TNFR1。我们假设 sTNF 通过 TNFR1 激活 SC，促进口腔癌 PNI 和神经性疼痛。我们的假设基于我们对患者、细胞培养物和动物模型的观察口腔癌和 PNI。该提案将结合肿瘤学、病理学、电生理学、细胞学等方面的专业知识生物学、神经超微结构、动物行为和统计学，旨在：目标 1. 评估 SC 之间的关联人类口腔癌中的激活、SC TNFR1 表达、PNI 和疼痛。目标 2. 表征 sTNF 的作用中和或 SC TNFR1 基因缺失对口腔癌疼痛的影响。我们将确定 sTNF-TNFR1 是否介导 SC 激活，导致 SC 释放伤害性介质，和/或伴随髓磷脂/轴突异常，导致伤害感受器过敏和神经性疼痛。目标 3. 表征 sTNF 中和或 SC TNFR1 基因缺失对口腔癌 PNI 的影响。我们将测试 sTNF- TNFR1 介导的 SC 激活促进 SC 和口腔之间的增殖、迁移和侵袭癌细胞，促进 PNI。我们的目标是阐明 SC 激活机制并测试控制 SC 激活以减少口腔癌 PNI 和疼痛的治疗潜力。了解 SC 如何导致口腔癌的 PNI 和神经性疼痛可能揭示新的机会和策略来中断口腔癌的这些并发症。